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Mechanisms of Apoptotic Induction by Iron Chelators Mechanisms of Apoptotic Induction By Iron Chelators Kirsteen Helen Maclean A thesis submitted to the University of London For the degree of Doctor of Philosophy 1999 The Department of Haematology University College London Medical School University College London 98 Chenies Mews LONDON WC1E6HX ProQuest Number: U642343 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U642343 Published by ProQuest LLC(2015). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract The orally bioavailable hydroxypyridinone iron chelator, CP20 (LI or deferiprone) is known to induce bone marrow hypoplasia and thymic aplasia in laboratory animals and apoptosis in thymocytes and leukaemic cell lines, although the mechanisms are unclear. Experiments contained within this thesis have sought to elucidate how iron chelators CP20 and Desferrioxamine (DFO) induce apoptosis in murine thymocytes, human leukaemic cells and haemopoietic progenitor cells. Inhibition of the iron (III) containing enzyme, ribonucleotide reductase (RR) with consequent inhibition of DNA synthesis has been examined as a possible mechanism of apoptotic induction. The apoptotic effects of the RR inhibitor, hydroxyurea, have been compared with those of the iron chelators in thymocytes, human leukaemic HL60 cells and human haemopoietic progenitors. Apoptosis has been compared in different cell types by quantitative flow cytometry. DNA synthesis inhibition has been assessed by the incorporation of both BrdU and ^H-thymidine. Whereas iron chelators induce thymocyte apoptosis as early as 4 hours, hydroxyurea showed no effect, suggesting that RR inhibition is not the primary apoptotic mechanism in this cell type. By contrast, both the chelators and hydroxyurea induced apoptosis in proliferating HL60 cells where BrdU analysis showed that for both HU and chelators the apoptotic population was derived from cells which had recently entered S phase. In haemopoietic progenitors derived from CD34^ peripheral blood cells in liquid culture, apoptosis was induced by HU and chelators only when the cells were in cycle (> days 2 or < 9 days of culture). These findings are consistent with inhibition of RR being causative in apoptotic induction in proliferating cells but not in thymocytes. In thymocytes, induction of apoptosis by chelators requires RNA and protein synthesis because actinomycin D and cycloheximide respectively abrogate this process. Chelator induced apoptosis was equal in p53 knockout and wild-type thymocytes, suggesting that primary DNA damage is not the apoptotic trigger. A possible link between chelation of zinc and the induction of apoptosis was also investigated. In thymocytes, zinc was shown to abrogate the apoptotic effects of chelators in vitro and in vivo. Furthermore prolonged exposure of thymocytes to chelators deprives the cells of intracellular zinc, indicating that zinc chelation may contribute to the apoptosis. The bidentate hydroxypyridinones interact with intracellular zinc pools at low concentrations (l|iM CP20) in a fundamentally different manner from the hexadentate iron chelator DFO. Unlike the latter chelator, CP20 can shuttle zinc from inaccessible sites within cells onto larger zinc chelating molecules thereby enhancing apoptosis. In conclusion, the findings in this thesis show that proliferating cells in S- phase are particularly susceptible to apoptotic induction by iron chelators. Furthermore because of the similarity in terms of cell specificity and kinetics of apoptosis between HU and iron chelators, inhibition of RR is a likely mechanism of apoptotic induction in proliferating cells. However in thymocytes which are predominantly non-proliferating, a different mechanism of apoptotic induction must be invoked, which may in part involve the chelation of zinc. To Mum and Dad For your constant love and support “Zeus who leads mortals on the road to understanding, Zeus who has ordained that wisdom comes through sujfering. Aeschylus-Agamemnon If I should labor through daylight and dark Consecrate, valorous, serious, true. Then on the world I may blazon my mark; And what if I don't and what if I do ? Philosophy by Dorothy Parker Acknowledgements A number of people have contributed both directly and indirectly to the production of this thesis and I would like to take this opportunity to express my gratitude to them. To. Novartis Pharmaceuticals, Basle, Switzerland for providing me with the funding for this work Dr. John Porter for his supervision, constructive critisism and giving me the opportunity to undertake such an interesting project Professor David Linch for his support in reading the manuscript Dr.s Rosemary Gale, Shaun Thomas and Asim Khwaja for reading the manuscript and helpful discussion Dr. Pam Roberts for her 'tea and sympathy' chats Mike Watts and Stuart Ings, thanks for the valuable CD34+ cells and all your computer know how Arnold Pizzey for his flow cytometry and computer expertise but more importantly for keeping me in touch with reality. Miss Louisa Hernandez for her calming words of wisdom The rest of the Dept. Haematology (you know who you are!) thank you for sparing me a few minutes of your time on the way to the toilet to ask about my well being and for asking the golden questions, 'Need a drink?', or 'How about a fag?', I am indebted to you all. Miss Katie McDonald for being my soul sister, a shoulder to cry on and keeping me sane during this frought period. All my friends outside of work, but at the end of a telephone (in particular Natasha, Adam and Steve) thank you for providing me with your kind words of encouragement Finally, my long-term love affair. Classic MAC, burglar proof, forever faithful??, the strong silent type. Will you ever forgive me for making you redundant now? INDEX PAGE TITLE PAGE 1 ABSTRACT 2 DEDICATION 4 ACKNOWLEDGEMENTS 5 INDEX 6 LIST OF FIGURES 13 LIST OF TABLES 16 ABBREVIATIONS 17 CHAPTER 1 GENERAL INFORMATION 20 1.1 INTRODUCTION 21 1.2 IRON BIOLOGY 21 1.3 IRON HOMEOSTASIS 2 3 1.3.1 Transferrin and iron transport 24 1.3.2 Ferritin and iron storage 2 6 1.3.3 Iron-dependent transcriptional control of ferritin and transferrin 2 7 1.3.4 Iron absorption 29 1.3.4.1 Intestinal cellular iron absorption 29 1.3.4.2Non-intestinal cellular iron uptake 31 1.4 IRON OVERLOAD 33 1.4.1 Iron mediated radical damage 3 3 1.4.2 Causes of iron overload 3 5 1.4.2.1 Idiopathic haemochromatosis 3 6 1.4.2.2Thalassaemia 36 1.4.2.2.1 a-Thalassaemia 37 1.4.2.2.2 p-Thalassaemia 3 8 1.5 IRON CHELATION 3 9 1.5.1 Sites of iron chelation 4 0 1.5.1.1 Extracellular iron 40 1.5.1.2Intracellular iron 4 0 1.5.2 Chelation therapy 41 1.5.2.1 Desferrioxamine 43 1.5.2.2Hydroxypiridinones 46 1.5.2.3Clinical consequences of chelation therapy 48 1.6 APOPTOSIS 49 1.6.1 Morphological characteristics of apoptosis 50 1.6.2 Biochemical characteristics of apoptosis 50 1.6.3 Apoptosis vs Necrosis 52 1.6.4 Apoptosis and disease 54 1.7 MOLECULAR BIOLOGY OF APOPTOSIS 55 1.7.1 Role of Caenorhabditis Elegans 55 1.7.2 Role of proteases in apoptosis 57 1.7.3 Substrates cleaved by caspases during apoptosis 59 1.7.4 Inhibitors of caspases 60 1.7.5 A caspase hierarchy 62 CHAPTER 2 GENERAL MATERIALS AND METHODS 65 2.1 GENERAL MATERIALS 6 6 2.2 IRON CHELATORS 66 2.3 CELL CULTURE 67 2.3.1 Cell lines 67 2.3.2 Cell counting and viability 67 2.3.3 Freezing and thawing of cells 68 2.3.4 Cytospin preparation of cells 68 2.3.5 Thymocyte isolation 68 2.3.6 Murine neutrophil isolation 68 2.3.7 CD34^ isolation 69 2.4 MEASUREMENT OF APOPTOSIS 70 2.4.1 Flow cytometric analysis 70 2.4.2 Agarose gel electrophoresis 70 2.5 MEASUREMENT OF INTRACELLULAR ZINC 71 2.6 DETERMINATION OF HAEMOPOIETIC SUBSETS 73 2.7 STATISTICAL ANALYSIS 73 CHAPTER 3 APOPTOTIC INDUCTION IN VARIOUS CELL TYPES BY IRON CHELATORS 74 3.1 INTRODUCTION 75 3.2 APOPTOTIC INDUCTION BY IRON CHELATORS IN THYMOCYTES 76 3.2.1 Rationale 76 3.2.2 General experimental procedure 7 6 3.2.3 Demonstration of apoptotic features by light microscopy 7 7 3.2.4 DNA fragmentation by agarose gel electrophoresis 7 7 3.2.5 Quantitative analysis of DNA fragmentation by flow cytometry 7 9 3.2.6 Identification of apoptosis by immunoanalysis in CD4+CD8+ thymocytes 81 3.2.7 Time dependence of chelator-induced apoptosis 8 4 3.2.8 Concentration dependence of chelator-induced apoptosis 8 7 3.2.9 Discussion 87 3.3 APOPTOTIC INDUCTION BY IRON CHELATORS IN CD34+ CELLS IN CULTURE 91 3.3.1 Rationale 91 3.3.2 Isolation and culture of CD34 cells 9 6 3.3.3 Changes in CD34 cells under conditions of culture, proliferation, differentiation and cell cycle profile 9 6 3.3.3.1 Changes in morphology under conditions of culture 9 6 3.3.3.2Changes in cell number under conditions of culture 9 9 3.3.3.3Changes in surface antigen expression under conditions of culture 9 9 3.3.3.4Changes in cell cycle status under conditions of culture 102 3.3.4 Effect on apoptosis of continuous exposure to chelators as measured by quantitative flow cytometry 102 3.3.5 Effect of duration in culture prior to incubation with chelators on apoptosis after 24h exposure 104 3.3.6 Effect
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